One-Year Outcomes in Survivors of the Acute Respiratory Distress Syndrome
Margaret S. Herridge, M.D., M.P.H., Angela M. Cheung, M.D., Ph.D., Catherine M. Tansey, M.Sc., Andrea Matte-Martyn, B.Sc., Natalia Diaz-Granados, B.Sc., Fatma Al-Saidi, M.D., Andrew B. Cooper, M.D., Cameron B. Guest, M.D., C. David Mazer, M.D., Sangeeta Mehta, M.D., Thomas E. Stewart, M.D., Aiala Barr, Ph.D., Deborah Cook, M.D., Arthur S. Slutsky, M.D., for the Canadian Critical Care Trials Group
Background As more patients survive the acute respiratory distresssyndrome, an understanding of the long-term outcomes of thiscondition is needed.
Methods We evaluated 109 survivors of the acute respiratorydistress syndrome 3, 6, and 12 months after discharge from theintensive care unit. At each visit, patients were interviewedand underwent a physical examination, pulmonary-function testing,a six-minute–walk test, and a quality-of-life evaluation.
Conclusions Survivors of the acute respiratory distress syndromehave persistent functional disability one year after dischargefrom the intensive care unit. Most patients have extrapulmonaryconditions, with muscle wasting and weakness being most prominent.
The acute respiratory distress syndrome is characterized bybilateral pulmonary infiltrates on frontal chest radiography,a ratio of arterial oxygen tension (PaO2) to the fraction ofinspired oxygen (FiO2) of 200 or less, and the absence of clinicalevidence of left atrial hypertension.1 As survival rates improveamong patients with the acute respiratory distress syndrome,2,3,4,5there is a growing need to understand the long-term effectsof this condition and its treatment.
Patients who survive the acute respiratory distress syndromeare at risk for physical and neuropsychological complicationsof the lung injury itself, associated multiorgan dysfunction,and their long stay in the intensive care unit (ICU). Severalinvestigators have evaluated morbidity among survivors usingpulmonary-function tests,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21neuropsychological and cognitive assessments,22,23,24,25,26and quality-of-life measures,27,28,29,30,31 and most have indicatedthat there is persistent morbidity after discharge from theICU. However, no study has prospectively performed individualizedassessments of physiological, functional, and quality-of-lifemeasures during the year after discharge from the ICU to ascertainthe main determinants of functional disability. Therefore, thegoal of this study was to characterize long-term pulmonary andextrapulmonary function in a prospectively identified cohortof patients who survived the acute respiratory distress syndrome.
Methods
Study Design
This longitudinal study was conducted at four university-affiliatedmedical–surgical ICUs in Toronto from May 1998 to May2002; the last patient completed his stay in the ICU in May2001. We identified potential patients from a prospective, dailyscreening log. Patients were eligible for enrollment if theywere at least 16 years of age, had a PaO2:FiO2 ratio of 200or less while receiving mechanical ventilation with a positiveend-expiratory pressure of at least 5 cm of water, evidenceof air-space changes in all four quadrants on chest radiography,and an identifiable risk factor for the acute respiratory distresssyndrome. Patients were excluded if they were immobile beforebeing admitted to the ICU, had a history of pulmonary resection,or had a documented neurologic or psychiatric disease.
We obtained written informed consent from the surrogate decisionmaker near the time of the patient's admission to the ICU. Writtenconsent for the one-year follow-up was obtained directly fromthe patient at the time of discharge from the ICU. This studywas approved by the institutional ethics committee at each ofthe participating hospitals.
Severity of Illness and Course in the ICU
We used the Acute Physiology, Age, and Chronic Health Evaluation(APACHE II)32 to determine the severity of illness within thefirst 24 hours after each patient was admitted to the ICU. Scorescan range from 0 to 71, with higher scores indicating more severeillness. We also determined the Multiple Organ Dysfunction Score33and a modified Lung Injury Score34 daily from day 0 (the dayof eligibility) to day 7 and then twice per week for the durationof the stay in the ICU. The Lung Injury Score is an aggregateof the score for the chest radiograph, hypoxemia, positive end-expiratorypressure, and respiratory-system compliance. Since respiratorycompliance was not measured as part of this study, a modifiedLung Injury Score was used, which consisted of the sum of thefirst three components. The Multiple Organ Dysfunction Scorecan range from 0 to 24, with higher scores indicating more severedysfunction. The Lung Injury Score can range from 0 to 4, withhigher scores indicating more severe lung injury. Other characteristicsof the patients during their stay in the ICU are outlined inTable 1.
Table 1. Characteristics of Patients with the Acute Respiratory Distress Syndrome (ARDS) at Enrollment and in the ICU, According to Whether They Survived to Discharge.
Follow-Up Protocol
We evaluated patients in an ambulatory clinic 3, 6, and 12 monthsafter they were discharged from the ICU. At each visit, thepatient was interviewed; underwent a physical examination, pulmonary-functiontesting, posteroanterior and lateral chest radiography, restingoximetry, and a standardized six-minute–walk test35 withcontinuous oximetry; and completed the Medical Outcomes Study36-item Short-Form General Health Survey (SF-36), which measuresthe health-related quality of life.36 The SF-36 includes eightmultiple-item scales that assess physical functioning, socialfunctioning, physical role, emotional role, mental health, pain,vitality, and general health. Scores for each aspect can rangefrom 0 (worst) to 100 (best). When a follow-up appointment wasmissed, the patient was given an opportunity to reschedule orrequest a home visit. Home visits were limited to a round-triptravel time of 10 hours from the greater Toronto area (approximately700 km). On home visits, pulmonary-function testing was limitedto spirometry and no chest radiograph was obtained.
Validation of Data
Inclusion and exclusion criteria were independently verifiedfor each patient by a principal investigator and a coinvestigatorat each ICU. Discrepancies were resolved by an ICU physicianwho was not involved in the study. We audited the data baseby obtaining a random sample of 10 percent of all charts andabstracting and independently verifying all ICU variables.
Statistical Analysis
The primary outcome measure of the study was the distance walkedin six minutes 3, 6, and 12 months after discharge from theICU. This measure provides a standardized, objective, integratedassessment of the cardiopulmonary and musculoskeletal systemthat is relevant to daily activities.35
A sample of 100 patients was required to demonstrate a differenceof 50 m in a six-minute–walk test at each follow-up betweenpatients with moderate lung injury (Lung Injury Score, lessthan 3.0) and those with severe lung injury (Lung Injury Score,3.0 or higher) with an alpha level of 0.05 and a statisticalpower of 80 percent. Since these outcomes have not been reportedfor survivors of the acute respiratory distress syndrome, webased our estimates on data from patients with chronic obstructivepulmonary disease. We used a difference of 50 m because thisis validated as a minimal clinically important difference amongpatients with chronic lung disease.37
We summarized continuous variables with medians and the 25thand 75th percentiles (the interquartile range) and used theWilcoxon rank-sum test for comparisons between survivors andthose who died. We summarized categorical variables using proportionsand 95 percent confidence intervals and used the Pearson chi-squaretest for comparisons between survivors and those who died. Weused Fisher's exact test when appropriate.
We performed univariate analyses to evaluate the potential determinantsof long-term function expressed as the distance walked in sixminutes. Multiple independent variables were identified a priori.Variables significant in the univariate analyses (P<0.2)were considered for inclusion in the multivariable linear regressionanalysis. We included age and sex in the final multivariablemodels because they are independent determinants of the distancewalked in six minutes.38 We performed the multivariate analysisusing a backward stepwise selection for each follow-up period(3, 6, and 12 months), and covariates remained in the multivariablemodel if the associated P value was less than 0.2. This wasdone to maximize the number of covariates in each model andincrease the variance explained (R2). SAS software (version8, SAS Institute) was used for all statistical analyses.
Results
Characteristics of the Patients
Over the 36-month recruitment period, we enrolled 198 of 228eligible patients. Reasons for exclusion are outlined in Figure 1.Two patients with prior pulmonary lobectomies and one patientwith a history of psychiatric disease were excluded after theaudit. Consent was obtained from 109 of 117 survivors, and thesepatients were included in the study (Figure 1).
Figure 1. Enrollment of Patients with the Acute Respiratory Distress Syndrome and Follow-up for the First 12 Months after Discharge from the ICU.
The actual median follow-up times for the visits at 3, 6, and12 months were 2.0, 7.1, and 12.6 months, respectively. Therate of in-person follow-up at the three-month visit was 80percent; 18 patients were not evaluated, because they were ina rehabilitation facility and inaccessible or because they declineda home visit. The rate of in-person follow-up at the 12-monthvisit was 86 percent. Forty-four percent of the patients receivedat least one home visit during the one-year follow-up period.Twelve patients died during the 12-month follow-up period, reflectinga 1-year mortality rate of 11 percent. Most deaths (9 of 12)occurred during the first six months after discharge from theICU and were related to preexisting medical problems. Threepatients died with multisystem organ failure, two died of hospital-acquiredpneumonia, one died suddenly at home, one died of respiratoryarrest, one of a pulmonary embolus, one of new-onset acute leukemia,one of hepatic failure, and two of unknown causes.
The median age of the patients with the acute respiratory distresssyndrome who survived to be discharged from the ICU was 45 years,and 56 percent were male (66 of 117) (Table 1). The APACHE IIscore, Lung Injury Score, and Multiple Organ Dysfunction Scorereflect the severity of illness in these patients. This groupof patients spent a median of 25 days in the ICU and 48 daysin the hospital. Twelve percent required renal-replacement therapyin the ICU. After discharge from the ICU, only one patient continuedto undergo dialysis, and this patient had end-stage renal diseaseat admission.
Global Assessment
At the time of discharge from the ICU, patients who survivedthe acute respiratory distress syndrome were severely wastedand had lost 18 percent of their base-line body weight (Figure 2).Seventy-one percent of patients (59 of 83) returned to theirbase-line weight by one year. All patients reported poor functionand attributed this to the loss of muscle bulk, proximal weakness,and fatigue. Most patients had alopecia, which resolved by sixmonths. Ten patients (12 percent) had marked and persistentpain at the sites of insertion of chest tubes at one year. Sixpatients (7 percent) had entrapment neuropathies. Four (5 percent)had enlargement and immobility of large joints as a result ofheterotopic ossification. Six (7 percent) were troubled by theappearance of their tracheostomy sites and had them surgicallyrevised. Three patients (4 percent) had contractured fingersor frozen shoulders because of immobility during their stayin the ICU. Two patients (2 percent) underwent successful treatmentof tracheal stenosis with laser excision of tissue.
Figure 2. Mean (+SE) Change in Weight from Base Line among Patients with the Acute Respiratory Distress Syndrome at the Time of Discharge from the ICU and at 3, 6, and 12 Months.
Pulmonary-Function Testing, Chest Radiography, and Oxygen Requirements
Patients had a mild restrictive pattern on lung-function testing,with a mild-to-moderate reduction in carbon monoxide diffusioncapacity at three months (interquartile range, 54 to 77 percentof the predicted values) (Table 2). Median carbon monoxide diffusioncapacity improved by 9 percentage points from month 3 to month12 (from 63 percent to 72 percent of the predicted value). Medianlung volume and spirometric measures were within 80 percentof the predicted values by six months. Because of weakness,six patients were unable to perform pulmonary-function testsat the three-month assessment. Chest radiographs were normalin 80 percent and revealed minor changes in 20 percent at oneyear. When present, radiologic changes included linear fibrosis,isolated areas of pleural thickening, and small, bullous cysts.None were receiving supplemental oxygen at the 12-month visit.Two patients were still receiving supplemental oxygen at thesix-month visit: one died shortly thereafter, and the otherno longer required oxygen at rest or on exertion after the six-monthappointment.
Table 2. Recovery of Pulmonary Function among Patients with the Acute Respiratory Distress Syndrome during the First 12 Months after Discharge from the ICU.
Table 3. Ability to Exercise and Return to Work and Health-Related Quality of Life among Patients with the Acute Respiratory Distress Syndrome during the First 12 Months after Discharge from the ICU.
Table 4. Predictors of Distance Walked in Six Minutes during the First 12 Months after Discharge from the ICU.
Quality of Life
The scores for all domains of the SF-36 improved from 3 to 12months after discharge from the ICU (Table 3). The scores forthe physical role and physical functioning domains improveddramatically during the year, paralleling the incremental improvementin the distance walked in six minutes. At one year, scores forall domains except emotional role were below those of an age-and sex-matched control population.39 At 3 months, 15 patientsdid not complete the SF-36 questionnaire, and 6 of those attributedthis to fatigue or weakness. At 6 and 12 months, six and threepatients, respectively, did not complete the questionnaire,and the reasons were not specified.
Relation between Patients' Characteristics and Distance Walked in Six Minutes
The results of univariate analyses are presented in Table 4.As compared with a Lung Injury Score of 3.0 or more, a scoreof less than 3.0 was significantly associated with a shorterdistance walked in six minutes at 6 months (P=0.009) but notat 3 months (P=0.98) or 12 months (P=0.82). Treatment with anysystemic corticosteroid during the admission to the ICU, thepresence of illness acquired during the ICU stay, and the rateof resolution of the lung injury and multiorgan dysfunctionduring the ICU stay (as reflected by the slope of the Lung InjuryScore and the Multiple Organ Dysfunction Score, respectively)were the most important determinants of the distance walkedin six minutes during the first year of follow-up.
We found that patients who survived the acute respiratory distresssyndrome have persistent functional limitation one year afterbeing discharged from the ICU, largely as a result of musclewasting and weakness and, to a lesser extent, to entrapmentneuropathy, heterotopic ossification, and intrinsic pulmonarymorbidity. Our results suggest that the inability to exerciseis primarily due to extrapulmonary disease; our impression isthat impaired muscle function had an important effect on thelong-term outcomes in these patients.
We postulate that the observed muscle wasting and weakness insurvivors of the acute respiratory distress syndrome is multifactorialand may be due in part to corticosteroid-induced and critical-illness–associatedmyopathy. The results of multivariate regression analysis supportthis hypothesis. At three months, we found that the use of anysystemic corticosteroid treatment is the main determinant ofthe ability to exercise. At six months, the effect of the useof systemic corticosteroids is lost and the burden of illnessacquired during the ICU stay and rate of resolution of illness(as reflected by the slopes of the Lung Injury Score and theMultiple Organ Dysfunction Score) become the important determinantsof exercise capacity. A variety of changes in the nerves, muscles,or neuromuscular junctions may also explain our findings ofmuscle wasting and weakness, such as anterior-horn cell lossas a result of hypoxic myelopathy, the polyneuropathy of criticalillness, atrophy or disuse myopathy resulting from prolongeduse of sedation and paralytic agents, mitochondrial myopathy,and prolonged post-paralysis syndrome.42
The results of the six-minute–walk test and quality-of-lifeassessments are consistent with data published previously. Cooperand colleagues noted decreases in the distance walked in sixminutes in a group of survivors of the acute respiratory distresssyndrome who were evaluated one to two years after they participatedin a trial of mechanical ventilation.43 Davidson and colleaguesfound that survivors of the acute respiratory distress syndromereported an important decrement in the physical functioningdomain of the SF-36 23 months after discharge from the intensivecare unit.30 Angus et al. demonstrated that the quality of lifeof these patients was compromised 6 and 12 months after hospitaldischarge.31 Impaired muscle function may explain the compromisedfunctional ability and quality of life in our cohort and thosestudied by other investigators.
Many studies of patients with the acute respiratory distresssyndrome have focused on pulmonary morbidity and have shownthat pulmonary function returns to normal or is nearly normalby six months to one year, with the exception of a persistentreduction in carbon monoxide diffusion capacity.6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,27A more recent study suggested that survivors of the acute respiratorydistress syndrome have important pulmonary symptoms and mayhave substantial limitations as a result of pulmonary diseaserelated to the syndrome.30
These variable results may be due to several factors. First,the heterogeneity of acute lung disease encompassed by the definitionof the acute respiratory distress syndrome may be an importantreason for reported differences in pulmonary sequelae. Somepatients in this cohort did not have diffuse alveolar damage.We found a 5 percent prevalence of bronchiolitis obliteransorganizing pneumonia and bronchiolitis obliterans. These caseswere diagnosed by open-lung biopsy, and treatment resulted ingood pulmonary function. If other cohorts had a significantprevalence of bronchiolitis obliterans organizing pneumoniaor bronchiolitis obliterans that went unrecognized and untreated,this might explain prior reports of pulmonary fibrosis and otherunfavorable pulmonary outcomes in other cohorts. Second, muscleweakness may account for the restrictive changes on pulmonary-functiontesting and symptoms of dyspnea, but we did not measure maximalinspiratory or expiratory efforts. Finally, the long-term effectof an episode of the acute respiratory distress syndrome maybe related to age and preexisting pulmonary function and maythus be cohort-specific. In our cohort of patients who survivedthe acute respiratory distress syndrome, the median age was45 years, few patients had important pulmonary dysfunction beforebecoming ill, and only 6 percent of patients had persistentpulmonary morbidity at one year.
We found that survivors of the acute respiratory distress syndromecontinue to have functional limitations one year after theirdischarge from the ICU. We still do not know how long it takesfor these patients to recover fully from their critical illnessor whether complete recovery is possible in every case. Sincewe did not follow a control group of ICU survivors who did nothave the acute respiratory distress syndrome, the sequelae weobserved may not be specific to the syndrome, but rather mayrepresent the typical residua of any severe, critical illness.Our data demonstrate the need for a detailed study of the natureof muscle wasting and weakness in these patients to determinewhether it is truly specific to the acute respiratory distresssyndrome and how we can change practices in the ICU and afterdischarge to ameliorate this disability.
Supported by the Canadian Intensive Care Foundation, the Physicians'Services Incorporated Foundation, the Ontario Thoracic Society,and a five-year Ontario Ministry of Health Health-Services ResearchCareer Scientist Award (to Dr. Cheung).
We are indebted to the patients and their families for theirwillingness to participate in the study, to Dr. Desmond Bohnfor his valuable advice, to Dr. Neill Adhikari for his assistancewith data validation, and to M. Steinberg, K. Sharma, G. DaCosta,S. DeSousa, D. Merker, D. Bowman, S. Grossman, R. MacDonald,B. Mehta, P. Chatrkaw, and D. Petrusic for their assistancewith recruitment and data collection.
Source Information
From the Department of Medicine, University Health Network (M.S.H., A.M.C., C.M.T., A.M.-M., F.A.-S.); the Interdepartmental Division of Critical Care Medicine (M.S.H., A.B.C., C.B.G., C.D.M., S.M., T.E.S., A.S.S.); the Department of Public Health Sciences (A.M.C., N.D.-G., A.B.); the Departments of Critical Care Medicine and Anaesthesia, Sunnybrook and Women's College Health Sciences Centre (A.B.C., C.B.G.); the Departments of Anesthesia and Critical Care Medicine (C.D.M.) and Medicine and Critical Care Medicine (A.S.S.), St. Michael's Hospital; the Departments of Medicine (S.M., T.E.S.) and Anesthesia (T.E.S.), Mount Sinai Hospital and the University of Toronto — all in Toronto; and the Departments of Medicine and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ont., Canada (D.C.).
Address reprint requests to Dr. Herridge at Toronto General Hospital, EN 10-212, 200 Elizabeth St., Toronto, ON M5G 2C4, Canada, or at margaret.herridge{at}uhn.on.ca.
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